Bacterial infection and primary biliary cirrhosis

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Cell Host Microbe. 2008 May 15;3(5):304-15.

Liver autoimmunity triggered by microbial activation of natural

killer T cells.

Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon

ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME,

Bendelac A

Medical Institute, Committee on Immunology, Department

of Pathology, University of Chicago, Chicago, IL 60637, USA; Division

of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH

45229, USA.

Humans with primary biliary cirrhosis (PBC), a disease characterized

by the destruction of small bile ducts, exhibit signature

autoantibodies against mitochondrial Pyruvate Dehydrogenase Complex

E2 (PDC-E2) that crossreact onto the homologous enzyme of

Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium.

Here, we show that infection of mice with N. aromaticivorans induced

signature antibodies against microbial PDC-E2 and its mitochondrial

counterpart but also triggered chronic T cell-mediated autoimmunity

against small bile ducts. Disease induction required NKT cells, which

specifically respond to N. aromaticivorans cell wall alpha-

glycuronosylceramides presented by CD1d molecules. Combined with the

natural liver tropism of NKT cells, the accumulation of N.

aromaticivorans in the liver likely explains the liver specificity of

destructive responses. Once established, liver disease could be

adoptively transferred by T cells independently of NKT cells and

microbes, illustrating the importance of early microbial activation

of NKT cells in the initiation of autonomous, organ-specific

autoimmunity.

PMID: 18474357

http://www.ncbi.nlm.nih.gov/pubmed/18474357